Alpha Thalassemia/mental Retardation Syndrome X-linked Mutations Research Articles

Oligoastrocytoma: The Vanishing Entity With True Dual Genotype, a Report, its Molecular Profiles and Review of Literature.

Isocitrate dehydrogenase (IDH) mutant gliomas are classified as astrocytoma or oligodendroglioma based on the recent application of ATRX mutation, TP53 mutation, and 1p/19q co-deletion. Astrocytomas classically show ATRX and TP53 mutations, whereas oligodendrogliomas are defined by 1p/19q co-deletion. However, there are reports of gliomas that harbor both astrocytoma and oligodendroglioma morphologically and molecularly. Here we present a patient of a 29-year-old woman who presented with a headache and underwent gross total excision. Magnetic resonance imaging showed a right frontal space-occupying lesion with T2 fluid-attenuated inversion recovery mismatch. Histology showed 2 distinct areas of morphology compatible with oligodendroglioma and astrocytoma. Immunohistochemistry showed both components being positive for IDH R132H. Alpha thalassemia/mental retardation syndrome X-linked (ATRX) showed loss of nuclear expression and p53 was strongly positive in the morphologic astrocytoma component, whereas ATRX was retained and p53 was negative in the morphologic oligodendroglioma component. Fluorescence in situ hybridization showed 1p/19q co-deletion in the oligodendroglioma component while co-deletion was absent in the astrocytoma component. TERT mutation was present in the oligodendroglioma component, whereas it was absent in the astrocytoma component. Although rare, gliomas harboring both oligodendroglioma and astrocytoma components in a single tumor exist and show genetically distinct areas.

Study of Molecular Markers in Glioma and Their Association with Clinicopathological Features.

Central nervous system tumors are a major cause of morbidity and mortality worldwide. The most prevalent type of primary brain tumor is glioma. The exploration of significant genetic, epigenetic, and transcriptional abnormalities has not only improved our understanding of glioma pathogenesis but has also revealed that these molecular alterations can serve as useful diagnostic markers for more precise classification and are linked to better treatment response and prognosis. Hence, incorporating molecular markers into routine tumor classification is a major priority in modern glioma diagnostics. The aim is to assess the mutation status of isocitrate dehydrogenase (IDH)-1, alpha-thalassemia/mental retardation syndrome X-linked (ATRX), and tumor protein 53 in glioma, and look for their association with various clinicopathological features. A single-center prospective cohort study, where all biopsies of glioma (January 2019 to July 2020) were evaluated, and immunohistochemistry was performed to assess the expression of IDH-1, ATRX, p53, and Ki-67 index. The data were analyzed using IBM SPSS-24 software. Immunohistochemistry was performed in 123 consecutive cases of glioma. IDH-1 mutation was noted in 54 (43.9%) cases and these patients frequently presented with "seizures" (P = 0.006). The expression was maximum in World Health Organization (WHO) grade 2 tumors (65.4%) (P < 0.001), with the highest frequency in oligodendrogliomas (100% in WHO grade 2 and 3). Furthermore, these tumors showed lower proliferative indices (P = 0.001). ATRX mutation was noted in 59 (48%) and p53 overexpression was noted in 76 (61.8%) cases. These mutations were significantly associated with astrocytic phenotype (P = 0.03). Molecular characterization of glioma is an important step in modern glioma diagnostics and immunohistochemistry can play an important role. IDH-1 mutation is commonly observed in adults, frontal lobe location, patients presenting with seizures, and WHO grade 2 tumors with the highest frequencies in oligodendrogliomas. ATRX and p53 can be used as surrogate markers for tumors of astrocytic lineage.

Pathological Evaluation of Diffuse Gliomas Using IDH1 and ATRX in a Resource-Limited Setting.

Classification of gliomas based on tumor histology remains the gold standard in the diagnosis and prognosis of gliomas. However, the recent World Health Organization (WHO) classificationhas included molecular studies for diagnosis and prognostication. Immunohistochemical markers such as isocitrate dehydrogenase 1 (IDH1) and alpha thalassemia/mental retardation syndrome X-linked (ATRX)can be used for the diagnosis andprognosis of the majority of gliomas. We aim to study the frequencies of IDH1 and ATRX mutations in diffuse gliomas using surrogate immunohistochemical markers and correlate histopathological findings of gliomas with immunohistochemical findings. This was a retrospective study of one-year duration from January 2022 to December 2022, conducted in the department of pathology. Relevant data was retrieved from medical records. Histopathology blocks were collected and sent for immunohistochemical studies using tissue microarray for IDH1 and ATRX. Qualitative data were expressed in percentages and proportions. The difference in proportion was calculated using the chi-square test, and a p-value of <0.005 was taken as significant. A total of 51 cases of diffuse gliomas were included in the study. The frequency of IDH1-positive diffuse astrocytomas was 33 (64.7%), and loss of ATRX was seen in 12 (23.5%) cases. Immunohistochemistry serves as a surrogate marker to detect molecular alterations in diffuse gliomas.

Multimodal-based machine learning strategy for accurate and non-invasive prediction of intramedullary glioma grade and mutation status of molecular markers: a retrospective study

BackgroundDetermining the grade and molecular marker status of intramedullary gliomas is important for assessing treatment outcomes and prognosis. Invasive biopsy for pathology usually carries a high risk of tissue damage, especially to the spinal cord, and there are currently no non-invasive strategies to identify the pathological type of intramedullary gliomas. Therefore, this study aimed to develop a non-invasive machine learning model to assist doctors in identifying the intramedullary glioma grade and mutation status of molecular markers. MethodsA total of 461 patients from two institutions were included, and their sagittal (SAG) and transverse (TRA) T2-weighted magnetic resonance imaging scans and clinical data were acquired preoperatively. We employed a transformer-based deep learning model to automatically segment lesions in the SAG and TRA phases and extract their radiomics features. Different feature representations were fed into the proposed neural networks and compared with those of other mainstream models. ResultsThe dice similarity coefficients of the Swin transformer in the SAG and TRA phases were 0.8697 and 0.8738, respectively. The results demonstrated that the best performance was obtained in our proposed neural networks based on multimodal fusion (SAG-TRA-clinical) features. In the external validation cohort, the areas under the receiver operating characteristic curve for graded (WHO I–II or WHO III–IV), alpha thalassemia/mental retardation syndrome X-linked (ATRX) status, and tumor protein p53 (P53) status prediction tasks were 0.8431, 0.7622, and 0.7954, respectively.ConclusionsThis study reports a novel machine learning strategy that, for the first time, is based on multimodal features to predict the ATRX and P53 mutation status and grades of intramedullary gliomas. The generalized application of these models could non-invasively provide more tumor-specific pathological information for determining the treatment and prognosis of intramedullary gliomas.

The chromatin remodeling protein ATRX positively regulates IRF3-dependent type I interferon production and interferon-induced gene expression.

The chromatin remodeling protein alpha thalassemia/mental retardation syndrome X-linked (ATRX) is a component of promyelocytic leukemia nuclear bodies (PML-NBs) and thereby mediates intrinsic immunity against several viruses including human cytomegalovirus (HCMV). As a consequence, viruses have evolved different mechanisms to antagonize ATRX, such as displacement from PML-NBs or degradation. Here, we show that depletion of ATRX results in an overall impaired antiviral state by decreasing transcription and subsequent secretion of type I IFNs, which is followed by reduced expression of interferon-stimulated genes (ISGs). ATRX interacts with the transcription factor interferon regulatory factor 3 (IRF3) and associates with the IFN-β promoter to facilitate transcription. Furthermore, whole transcriptome sequencing revealed that ATRX is required for efficient IFN-induced expression of a distinct set of ISGs. Mechanistically, we found that ATRX positively modulates chromatin accessibility specifically upon IFN signaling, thereby affecting promoter regions with recognition motifs for AP-1 family transcription factors. In summary, our study uncovers a novel co-activating function of the chromatin remodeling factor ATRX in innate immunity that regulates chromatin accessibility and subsequent transcription of interferons and ISGs. Consequently, ATRX antagonization by viral proteins and ATRX mutations in tumors represent important strategies to broadly compromise both intrinsic and innate immune responses.

Diagnostic algorithm for pathological evaluation of gliomas in a resource-constrained setting.

Gliomas are the most common primary intracranial tumors. The current World Health Organization (WHO) classification of central nervous system tumors recommends integrated histo-molecular diagnosis of gliomas. However, molecular testing is not available in even most of the advanced centers of our country, and histopathology aided with immunohistochemistry (IHC) is still widely used for diagnosis. Immunohistochemical markers such as iso-citrate dehydrogenase1 (IDH1) and Alpha Thalassemia/Mental Retardation Syndrome X-linked (ATRX) can be reliably used for the correct diagnosis, prognosis, and treatment of gliomas. We aimed to develop a diagnostic algorithm by integrating morphology, IDH1, and ATRX status of gliomas seen in our institute for 1 year. Analytical cross-sectional study. This study included 60 histopathologically confirmed cases of astrocytic (n = 51) and oligodendroglial tumors (n = 9). Clinical, radiological, and histopathological features were noted and tumor grades assigned according to the WHO recommendations. IDH1 and ATRX mutation status was evaluated using IHC. The tumors were divided into three molecular groups on the basis of their IDH1 and ATRX mutation status: (1) Group 1: IDH1 negative and ATRX positive, (2) Group 2: IDH1 positive and ATRX positive, (3) Group 3: IDH1 positive and ATRX negative. The mean age of presentation was 45.0 ± 15.8 years with a male-to-female ratio of 2:1. Seizures, headache, and hemiparesis were the most common modes of presentation. The tumor subtypes studied were glioblastoma (n = 32), anaplastic astrocytoma (n = 7), diffuse astrocytoma (n = 6), oligodendroglioma (n = 6), pilocytic astrocytoma (n = 6), and anaplastic oligodendroglioma (n = 3). IDH1 mutation was present in 26 cases including anaplastic astrocytoma (n = 7), diffuse astrocytoma (n = 6), oligodendroglioma (n = 5), secondary glioblastoma (n = 5), and anaplastic oligodendroglioma (n = 3). ATRX mutation, i. e., loss of ATRX was observed in 17 cases including diffuse astrocytoma (n = 5), anaplastic astocytoma (n = 5), anaplastic oligodendroglioma (n = 3), oligodendroglioma (n = 3), and secondary glioblastoma (n = 1). All six cases of pilocytic astrocytoma were negative for IDH1 and ATRX mutation. There were 34 patients in Group 1 (IDH1- and ATRX +), nine cases in Group 2 (IDH1 + and ATRX +), and 17 patients in Group 3 (IDH1 + and ATRX-). Diagnosis of gliomas should be based on a detailed clinicoradiological and histopathological assessment, followed by genotypic characterization. Evaluation for IDH1and ATRX status has both diagnostic and prognostic value as it helps in differentiating gliomas from reactive gliosis, primary glioblastoma from secondary glioblastoma, and pilocytic astrocytoma (WHO grade I) from diffuse astrocytoma (WHO grade II). Tumors with IDH1 mutations have a better outcome than those with wild-type IDH. IHC can serve as a useful surrogate to conventional molecular tests in resource-constrained settings. By devising an algorithm based on morphological and IHC features, we were able to stratify gliomas into three prognostic subgroups.

Loss of ATRX confers DNA repair defects and PARP inhibitor sensitivity

Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) is mutated frequently in gliomas and represents a potential target for cancer therapies. ATRX is known to function as a histone chaperone that helps incorporate histone variant, H3.3, into the genome. Studies have implicated ATRX in key DNA damage response (DDR) pathways but a distinct role in DNA repair has yet to be fully elucidated. To further investigate the function of ATRX in the DDR, we created isogenic wild-type (WT) and ATRX knockout (KO) model cell lines using CRISPR-based gene targeting. These studies revealed that loss of ATRX confers sensitivity to poly(ADP)-ribose polymerase (PARP) inhibitors, which was linked to an increase in replication stress, as detected by increased activation of the ataxia telangiectasia and Rad3-related (ATR) signaling axis. ATRX mutations frequently co-occur with mutations in isocitrate dehydrogenase-1 and -2 (IDH1/2), and the latter mutations also induce HR defects and PARP inhibitor sensitivity. We found that the magnitude of PARP inhibitor sensitivity was equal in the context of each mutation alone, although no further sensitization was observed in combination, suggesting an epistatic interaction. Finally, we observed enhanced synergistic tumor cell killing in ATRX KO cells with ATR and PARP inhibition, which is commonly seen in HR-defective cells. Taken together, these data reveal that ATRX may be used as a molecular marker for DDR defects and PARP inhibitor sensitivity, independent of IDH1/2 mutations. These data highlight the important role of common glioma-associated mutations in the regulation of DDR, and novel avenues for molecularly guided therapeutic intervention.

Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations.

ContextAggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors.ObjectiveTo study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs.DesignWe investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored.ResultsNine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs.Conclusion ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors.

Prognostic factors in progressive high-grade glial tumors treated with systemic approach: A single center experience

Malignant high-grade gliomas are the most common and aggressive type of primary brain tumor, and the prognosis is generally extremely poor. In this retrospective study, we analyzed the outcome of systemic treatment in recurrent high-grade glioma patients and the impact of prognostic factors on survivals. Data from 114 patients with recurrent high-grade glioma who received systemic treatment and followed in our clinic between 2012 and 2018 were retrospectively analyzed. Eastern Cooperative Oncology Group (ECOG) performance status, age, gender, histology, type of surgical resection, side effects after systemic treatment (deep vein thrombosis, hypertension, proteinuria), IDH1 and alpha thalassemia/mental retardation syndrome X-linked (ATRX) mutation status were investigated as prognostic factors for progression-free survival and overall survival. At the time of diagnosis, the median age was 48 (17-77) and 68% of the patients were male. Most common pathologic subtype was glioblastoma multiforme (68%). Median follow-up duration was 9.1 months (1-68 months). Median progression-free survival and overall survival were 6.2 months and 8 months, respectively. In multivariate analysis, ECOG PS, deep venous thrombosis and the presence of ATRX and IDH1 mutation were found to be independent prognostic factors for progression-free survival (p < 0.05) and, ECOG PS, the presence of ATRX and IDH1 mutation for overall survival (p < 0.05). Our study is real life data and the median progression-free survival and overall survival rates are similar to the literature. We have found ECOG PS, presence of ATRX and IDH1 mutation to be independent prognostic factors for both progression-free survival and overall survival.

Correlation between IDH, ATRX, and TERT promoter mutations in glioma.

According to the 2016 World Health Organization (WHO) classification of central nervous system tumors, diffuse astrocytic and oligodendroglial tumors are differentiated by the presence of isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation and the combined loss of the short arm of chromosome 1 and the long arm of chromosome 19 (1p/19q co-deletion). IDH-mutant astrocytoma often has p53 and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutation, showing the alternative lengthening of telomeres (ALT) phenotype, while IDH-mutant and 1p/19q-co-deleted oligodendroglioma often have wild-type p53 and telomerase reverse transcriptase (TERT) promoter mutation, showing telomerase activation. This study analyzed IDH, ATRX, and TERT promoter mutations, and the correlation between them. Immortalized cells overcome the telomere-related crisis by activating telomerase or ALT. In glioma, telomerase is mainly activated by TERT promoter mutation, while ALT is usually associated with ATRX mutation. Although the mechanism of how ATRX mutation induces ALT remains unclear, ATRX loss alone is believed to be insufficient to induce ALT. Treatments targeting telomere maintenance are promising.

Epitope mapping of an anti-alpha thalassemia/mental retardation syndrome X-linked monoclonal antibody AMab-6

The alpha-thalassemia/mental-retardation-syndrome-X-linked (ATRX) gene is located on the q arm of the X chromosome. ATRX gene mutations were first discovered in pancreatic neuroendocrine tumors, and subsequently in other cancer subtypes, including gliomas. Molecular subgrouping of gliomas has been more important than conventional histological classifications. Mutations in the isocitrate dehydrogenase (IDH), telomerase reverse transcriptase (TERT) promoter, and ATRX and the codeletion of chromosomes 1p/19q are used as biomarkers for diagnosing the subtypes of diffuse gliomas. We recently developed a sensitive monoclonal antibody (mAb) AMab-6 against ATRX by immunizing mice with recombinant human ATRX. AMab-6 can help to detect ATRX mutations via Western blotting and immunohistochemical analyses. In this study, we characterized the binding epitope of AMab-6 using enzyme-linked immunosorbent assay (ELISA), Western blotting, and immunohistochemical analysis, and found that Gln2368 of ATRX is critical for AMab-6 binding to ATRX. Our findings could be applied to the production of more functional anti-ATRX mAbs.

Alpha Thalassemia/Mental Retardation Syndrome X-Linked, the Alternative Lengthening of Telomere Phenotype, and Gliomagenesis: Current Understandings and Future Potential.

Gliomas are the most common primary malignant brain tumor in humans. Lower grade gliomas are usually less aggressive but many cases eventually progress to a more aggressive secondary glioblastoma (GBM, WHO Grade IV), which has a universally fatal prognosis despite maximal surgical resection and concurrent chemo-radiation. With the identification of molecular markers, however, there is promise for improving diagnostic and therapeutic strategies. One of the key molecular alterations in gliomas is the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, which is frequently mutated. One-third of pediatric GBM cases are also found to have the ATRX mutation and the genetic signatures are different from adult cases. The exact role of ATRX mutations in gliomagenesis, however, is unclear. In this review, we describe the normal cellular function of the ATRX gene product followed by consequences of its dysfunction. Furthermore, its possible association with the alternative lengthening of telomeres (ALT) phenotype is outlined. Lastly, therapeutic options potentiated through a better understanding of ATRX and the ALT phenotype are explored.

New Molecular Considerations for Glioma: IDH, ATRX, BRAF, TERT, H3 K27M

This review will discuss the role of several key players in glioma classification and biology, namely isocitrate dehydrogenase 1 and 2 (IDH1/2), alpha thalassemia/mental retardation syndrome X-linked (ATRX), B-Raf (BRAF), telomerase reverse transcriptase (TERT), and H3K27M. IDH1/2 mutation delineates oligoden-droglioma, astrocytoma, and secondary glioblastoma (GBM) from primary GBM and lower-grade gliomas with biology similar to GBM. Additional mutations including TERT, 1p/19q, and ATRX further guide glioma classification and diagnosis, as well as pointing directions toward individualized treatments for these distinct molecular subtypes. ATRX and TERT mutations suggest the importance of telomere maintenance in gliomagenesis. BRAF alterations are key in certain low-grade gliomas and pediatric gliomas but rarely in high-grade gliomas in adults. Histone mutations (e.g., H3K27M) and their effect on chromatin modulation are novel mechanisms of cancer generation and uniquely seen in midline gliomas in children and young adults. Over the past decade, a remarkable accumulation of knowledge from the genomic study of gliomas has led to reclassification of tumors, new understanding of oncogenic mechanisms, and novel treatment strategies.

MPTH-30ATRX CAN OCCUR IN IDH WILD-TYPE GBM

BACKGROUND: ATRX (alpha thalassemia/ mental retardation syndrome X-linked) is a transcriptional regulatory protein which contains an ATPase/helicase domain. In gliomas loss of ATRX expression has been recently described and is mostly restricted to IDH mutant tumors who seem to have a significantly better prognosis. ATRX loss is thought to be extremely rare in IDH wild type (WT) tumors and in that setting one group reported H3F3A mutation. METHODS: Tissue samples of 23 patients with IDH wild-type malignant gliomas were analyzed for ATRX expression using immunohistochemistry. ATRX status was associated with clinical characteristics, histology and other molecular markers (MGMT, BRAF, EGFR). RESULTS: Median age in all patients was 49,3 years. Loss of ATRX expression was detected in 4 out of 23 patient tumors. All ATRX loss patients were primary glioblastomas. Median survival in ATRX mutated gliomas is 237 weeks which was longer than overall survival in gliomas with retained ATRX (88 weeks). All of our patients underwent concurrent chemoradiotherapy with temozolomide. One out of four ATRX loss tumors was BRAF mutated, three out of four ATRX loss patients tested for EGFR were found to be wild type and the two ATRX mutated patients tested for MGMT were methylated. CONCLUSION: ATRX mutation can occur in IDH wild-type patients. In that setting it appears to be associated with a better outcome. Our data is hypothesis generating. Tumors with IDH WT/ ATRX loss should be evaluated prospectively in a larger cohort and possibly checked for H3F3A mutation.

O8.06 * ATRX AND TERT EXPRESSION IN RELAPSING LOW GRADE GLIOMA

Mechanisms responsible for telomere maintenance are been recently elucidated: many cancers harbor mutations in alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene resulting in a phenomenon known as alternative lengthening of telomeres (ALT) or point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene leading to an increased telomerase expression. ATRX and TERT mutations have been recently identified also in brain tumors. In gliomas, a molecular stratification based on IDH and ATRX mutational status and 1p/19q codeletion has been suggested. ATRX mutations have been observed mainly in astrocytic tumors and TERT promoter mutations mainly in oligodendroglial tumors. Aim of our study was to evaluate the expression of both ATRX and TERT in WHO grade II gliomas and in their resected recurrences, related to a set of confirmed molecular markers and to clinical data. We performed an immunohistochemical analysis of ATRX and TERT expression in 30 grade II gliomas (astrocytomas, oligoastrocytomas and oligodendroglioma) and in their respective recurrences (grade III-IV). Also evaluation of IDH1 and p53 status and 1p/19q LOH were carried out. Loss of expression of ATRX protein has been associated to the mutated gene and ALT phenotype, while expression of TERT protein could be related to TERT promoter mutations. We found a loss of ATRX expression in 70% of cases; recurrences showed the same pattern of ATRX expression. In the most part of cases ATRX loss was associated to IDH1 and p53 mutation and intact 1p/19q, as previously observed. In the major part of cases with ATRX loss of expression TERT was not detected. TERT high expression was observed in about 30% of grade II gliomas at the first surgery, minor expression of TERT was found in grade III-IV recurrent tumors. In most case high expression of TERT was associated to 1p/19q deletion. We observed a statistically significant correlation between TERT high expression and a better outcome. Our study of protein expression of both ATRX and TERT in low grade gliomas and in their recurrences in relationship with established molecular markers and follow-up data, confirm the possibility of using immunohistochemistry in routine diagnostic procedures for better define this subset of neoplasm.

TERT PROMOTER MUTATIONS OCCUR FREQUENTLY IN GLIOMAS AND A SUBSET OF TUMORS DERIVED FROM CELLS WITH LOW RATES OF SELF-RENEWAL

c Neurosurgery, d Otolaryngology—Head and Neck Surgery, h Pathology, l Urology, and m Malignant cells, like all actively growing cells, must maintain their telomeres, but genetic mechanisms responsible for telomere main- tenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/ mental retardation syndrome X-linked (ATRX )o rdeath-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telo- merase expression and have been shown to occur in melanomas and a small number of other tumors. To further define the tumor types in which this latter mechanism plays a role, we surveyed 1,230 tumors of 60 different types. We found that tumors could be divided into types with low (<15%) and high (≥15%) frequen- cies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carci- nomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas (including 83% of primary glioblastoma, the most common brain tumor type). TERT and ATRX mutations were mutually exclusive, suggest- ing that these two genetic mechanisms confer equivalent selective growth advantages. In addition to their implications for under- standing the relationship between telomeres and tumorigenesis, TERT mutations provide a biomarker that may be useful for the early detection of urinary tract and liver tumors and aid in the classification and prognostication of brain tumors.